Clinical development of the GnRH agonist leuprolide acetate depot

The CPP results from premature pubertal activation of the hypothalamic-pituitary-gonadal axis resulting in the pulsatile release of GnRH and premature secretion of gonadal steroids in both girls and boys. Treatment with GnRH agonists has been the standard of care for CPP for more than 30 years ( 21 ). Treatment results in hormonal suppression, cessation of pubertal development, and normalization of growth and skeletal maturation rates. Leuprolide acetate was the first GnRH agonist used for the treatment of CPP ( 22 , 23 ). It was initially developed as monthly intramuscular injections (7.5, 11.25, and 15 mg) and later as 3-month intramuscular injections (11.25 and 30 mg). It is available in the United States under the brand name Lupron Depot-Ped(R) ( Table 1 ). The dose selection is based on child weight for both 1-month and 3-month formulations ( 6 ). It was established during clinical phase III studies performed in the United States. Biochemical (peak-stimulated luteinizing hormone, estradiol in girls, and testosterone in boys) and anthropometric (growth rate, bone age acceleration, pubertal progression) parameters and safety were assessed in these studies. The safety and efficacy of leuprolide acetate 1-month depot formulations have been established in children with CPP ( 6 , 23 ). Subsequently, the 3-month depot formulations were evaluated in phase III, a randomized, open-label study in children (n = 84) with CPP ( 24 , 25 ). This study concluded that treatment with leuprolide acetate 3-month depot formulations effectively suppressed the GnRH axis and may positively affect patient convenience and compliance. Both 1- and 3-month depot formulations were well-tolerated, with injection site pain being the most frequent treatment-emergent adverse event.

This review is based on a PubMed search for human studies with leuprolide acetate conducted between 1985 and 2022, focusing on registration phase II and phase III studies and gynecological indications.

One of the key discoveries in GnRH research was the observation that native GnRH is secreted from the hypothalamus in a pulsatile manner and the frequency of its pulses determines whether follicle-stimulating hormone or luteinizing hormone is secreted from the pituitary gland ( 9 ). Depot formulations of GnRH agonists provide continuous stimulation of the GnRH receptors that, after an initial stimulatory phase, consequently leads to their desensitization resulting in profound suppression of gonadotropins and ovarian steroids ( Fig. 1 ) ( 10 ). This unexpected effect provided the rationale for suppressive therapies in various clinical indications. FIGURE 1 Mechanism of action of GnRH, depot GnRH agonists and GnRH antagonists. The figures in the upper level present the interaction of native GnRH ( A ), depot GnRH agonists ( B ) and GnRH antagonists ( C ) with the GnRH-R in the pituitary gland. The corresponding figures in the lower level present relative estradiol suppression. ( A ) Native GnRH is released in a pulsatile manner from the hypothalamus. The frequency of GnRH pulses regulates cyclic changes in gonadotropins (LH, FSH) and estradiol concentrations during the cycle. ( B ) Depot GnRH agonists initially stimulate the HPO axis, which results in a transient hormonal flare. Continued stimulation of GnRH-R consequently leads to their desensitization and profound estradiol suppression. ( C ) GnRH antagonists competitively bind to GnRH-R and produce rapid and dose-dependent suppression of the HPO axis, which results in a partial estradiol suppression at lower doses to nearly full suppression at higher doses. FSH = Follicle-stimulating hormone; GnRH = Gonadotropin-releasing hormone; GnRH-R = GnRH receptor; HPO = Hypothalamo–pituitary–ovarian; LH = Luteinizing hormone. (From Taylor et al. [ 10 ]. Reprinted by permission of the publisher.) Mechanism of action of GnRH, depot GnRH agonists and GnRH antagonists. The figures in the upper level present the interaction of native GnRH ( A ), depot GnRH agonists ( B ) and GnRH antagonists ( C ) with the GnRH-R in the pituitary gland. The corresponding figures in the lower level present relative estradiol suppression. ( A ) Native GnRH is released in a pulsatile manner from the hypothalamus. The frequency of GnRH pulses regulates cyclic changes in gonadotropins (LH, FSH) and estradiol concentrations during the cycle. ( B ) Depot GnRH agonists initially stimulate the HPO axis, which results in a transient hormonal flare. Continued stimulation of GnRH-R consequently leads to their desensitization and profound estradiol suppression. ( C ) GnRH antagonists competitively bind to GnRH-R and produce rapid and dose-dependent suppression of the HPO axis, which results in a partial estradiol suppression at lower doses to nearly full suppression at higher doses. FSH = Follicle-stimulating hormone; GnRH = Gonadotropin-releasing hormone; GnRH-R = GnRH receptor; HPO = Hypothalamo–pituitary–ovarian; LH = Luteinizing hormone. (From Taylor et al. [ 10 ]. Reprinted by permission of the publisher.)

Leuprolide acetate was the first GnRH agonist that entered clinical development as daily subcutaneous injections in men with advanced prostate cancer and was approved by the FDA in 1985. Successively, several long-acting depot formulations of leuprolide acetate (ranging from 1-month to 6-month, depending on indication) have been developed for various indications in men, women, and children, including palliative treatment of prostate cancer, management of endometriosis, preoperative treatment of women with anemia and fibroids, and CPP. These formulations are available in the United States under the tradenames of Lupron Depot and Lupron Depot-Ped.